International Journal of Reproduction, Contraception, Obstetrics and Gynecology Luthra S et al. Int J Reprod Contracept Obstet Gynecol. 2018 Sep;7(9):3610-3614 www.ijrcog.org pISSN 2320-1770 | eISSN 2320-1789 DOI: http://dx.doi.org/10.18203/2320-1770.ijrcog20183762 Original Research Article Dysfunctional uterine bleeding: ormeloxifene versus combined oral contraceptive pills

Sonia Luthra*, A. D. Dwivedi

Department of Obstetrics and Gynecology, Hind Institute of Medical Sciences, Safedabad, Barabanki, Uttar Pradesh, India

Received: 13 June 2018 Accepted: 07 July 2018

*Correspondence: Dr. Sonia Luthra, E-mail: [email protected]

Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: Dysfunctional uterine bleeding is abnormal bleeding that occurs in the absence of recognizable pelvic pathology, general medical disease, or pregnancy. Globally, health care systems are focusing on low morbidity and low cost therapeutic interventions. Hence, medical treatment for DUB is high on the priority list. This comparative study was conducted to analyse the efficacy of ormeloxifene and combined oral contraceptive pills in reducing the blood loss and endometrial thickness in cases of DUB. Methods: This prospective study was conducted on women with dysfunctional uterine bleeding, who attended Gynaecology OPD at Hind Institute of Medical Sciences, between August 2015 and April 2016. After applying inclusion and exclusion criteria, 72 women diagnosed with DUB were enrolled randomly in two groups A and B. Group A was treated by Ormeloxifene and Group B patients were treated with combined oral contraceptive pills for three consecutive cycles. The efficacies of the studied drugs were compared by analyzing the mean change in the pre and post treatment PBAC score, haemoglobin level and endometrial thickness using unpaired t-test. Results: Ormeloxifene was found to be significantly more effective (p <0.0001) than OCPs in controlling the menstrual blood loss (79% reduction in group A Vs 55.5% reduction in group B). Reduction in endometrial thickness

was also more in the group receiving Ormrloxifene, however this was statistically not significant (p = 0.19). No major side effect observed with the use of Ormeloxifene.

Conclusions: Ormeloxifene can be an effective and safe therapy in the treatment of Dysfunctional uterine bleeding.

Keywords: Dysfunctional uterine bleeding, Oral contraceptive pills, Ormeloxifene, Selective estrogen receptor modulator

INTRODUCTION of debility like DUB has adverse economic, social and personal consequences. Abnormal uterine bleeding is a significant health care problem for women, their families, and society as a Dysfunctional uterine bleeding is abnormal bleeding that whole. Up to 30% of women will seek medical assistance occurs in the absence of recognizable pelvic pathology, for this problem during their reproductive years.1 Because general medical disease, or pregnancy. It reflects a most cases are associated with anovulatory menstrual disruption in the normal cyclic pattern of hormonal cycles, adolescents and perimenopausal women are stimulation to the endometrial lining which is thought to particularly vulnerable.2,3 In today’s world, where women be caused by dysfunction of hypothalamic-pituitary- represent a major sector of paid force in both the ovarian axis.4 DUB is a frequent indication for developing and developed countries, any regular source hysterectomy in developing countries.5 Globally, health

September 2018 · Volume 7 · Issue 9 Page 3610 Luthra S et al. Int J Reprod Contracept Obstet Gynecol. 2018 Sep;7(9):3610-3614 care systems are focusing on low morbidity and low cost • AUB cases having no evidence of pelvic pathology therapeutic interventions. Hence, medical treatment for on clinical examination or USG. DUB is high on the priority list. Exclusion criteria Medical management of DUB is a challenging task. The options for initial management of DUB include • Pregnancy related bleeding like abortion or ectopic antifibrinolytics, nonsteroidal anti-inflammatory drugs pregnancy (NSAIDs), combined estrogen and progesterone pills, • Hypersensitivity to the drug progesterones alone, high dose estrogens, gonadotropin- • Any hormonal therapy including oral contraceptive releasing hormone agonists, danazol and levonorgesterol pill usage within last 3 months releasing intrauterine systems. Cyclical combined oral • Any IUCD used or removed within last 6 months. contraceptive pills are widely used but side effects, • Positive cervical cytology and colposcopic especially in women over 40 years of age, have restricted examination or suspicious cervix their use. Danazol, progesterone and gonadotropin- • History of breast malignancy or any palpable lump in releasing hormone analogues are all effective in terms of breasts reducing menstrual blood loss, but adverse effects and • Current genital infection costs limit their long-term use. • Active bleeding necessitating emergency treatment • Patient with severe anaemia (Hb <6 gm %) For the treatment of DUB authors need a drug, which • Any systemic diseases such as liver disorders, blocks the action of estrogen on endometrium(anti- platelet disorder or coagulopathy estrogenic) but not its beneficial actions on other tissues. Selective estrogen receptor modulators (SERMs) have • Previous history of thrombosis or of migraine. been identified to occupy a place in between estrogens and antiestrogens. Selected patients of dysfunctional uterine bleeding who consented for drug trial study and for regular follow up, These compounds have estrogenic activities, which are were included in the study and were divided into tissue selective. Ormeloxifene is an optimally designed following two groups: SERM, which behaves like an estrogen antagonist in uterus with mild estrogenic action on vagina, bone and Group A (Ormeloxifene group): serum lipids.6-8 Thus, it is especially beneficial in perimenopausal women as it has no uterine stimulation, It was comprised of 36 patients who were prescribed prevents bone loss, does not increase the risk of breast Ormeloxifene 60 mg twice a week for twelve weeks. cancer, lowers cholesterol level and maintains cognitive function of the brain. It has the additional advantage of Group B (Combined oral contraceptive group): reducing premenstrual symptoms, dysmenorrhoea and mastalgia.9 This group was comprised of 36 patients who were prescribed combined oral contraceptive pills (containing When ormeloxifene was used as a contraceptive, its ethinyl estradiol 30 μg and levonorgestrel 0.3 mg) for beneficial effects on menorrhagia and endometriosis were twenty-one days starting from third day of menses observed, which led to controlled trials for the followed by seven pill free days. This treatment was management of menorrhagia after approval was given by continued for three consecutive cycles. the Indian Drug Regulatory Authorities for this indication. All women were instructed to use sanitary napkin of similar kind, not containing absorbent gel. A detailed METHODS menstrual history and physical examination was done at each visit at monthly interval. Any side effects observed A prospective study was conducted on women who were were noted. The subjective improvement of symptoms diagnosed as a case of dysfunctional uterine bleeding at and acceptability of drugs were enquired. The efficacy of out-patient department of Obstetrics and Gynaecology at drugs, subjective and objective findings of improvement Hind Institute of Medical Sciences, Safedabad, Barabanki in the condition of patient, tolerance to the drug and side between August 2015 and April 2016. effects were noted.

Out of total of 345 cases of abnormal uterine bleeding, The main outcome to be measured were menstrual blood 115 were found to have DUB. Total 72 patients were loss by PBAC score, blood hemoglobin levels in gm/dl selected according to exclusion and inclusion criteria. and endometrial thickness in mm, on 18-21 day of Written informed consent for drug trial was taken. menstrual cycle by trans-vaginal sonography (TVS).

Inclusion criteria Pictorial Blood loss Assessment Chart (PBAC) (Higham et al., 1990) 10 was used to measure the menstrual blood • Women between menarche and menopause loss (MBL). Scores were assigned to different degrees of

International Journal of Reproduction, Contraception, Obstetrics and Gynecology Volume 7 · Issue 9 Page 3611 Luthra S et al. Int J Reprod Contracept Obstet Gynecol. 2018 Sep;7(9):3610-3614 soiling of sanitary napkins and number and size of clots significant reduction in mean PBAC score from 258.44 to passed at every cycle as per Figure 1. 54.24 i.e. 79% reduction in menstrual blood loss. Similarly, a significant reduction in endometrial thickness was seen after treatment (P value<0.0001). A significant improvement in anemia was also seen inspite of no iron therapy given along with Ormiloxifene therapy (Figure 2).

In Combined oral contraceptive group (group B, N=28), p value <0.0001 indicates significant reduction in mean PBAC score from 221.34 to 98.45 (55.5%) after treatment. A significant reduction in endometrial thickness (P <0.0001) was also seen. A significant rise in haemoglobin level was observed (P<0.0001) after three months treatment with combined oral contraceptive pills, with no iron supplementation (Figure 3). On comparing group, A and group B, ormeloxifene was found significantly better than combined OCP in reduction of menstrual blood loss (79% vs 55.52% reduction with p Figure 1: Blood loss assessment chart. value <0.0001) in cases of DUB. Reduction in mean endometrial thickness was also better in Ormeloxifene Statistical analysis group than in combined OCPs group, but statistically it was not found significant (p value- 0.19). PBAC score, haemoglobin concentration and endometrial thickness were measured before the start of therapy and 221.34 at end of 3 months i.e. after the completion of therapy. 250 Statistical parameters were used as Mean±Standard Deviation and data were analysed using the paired t test. 200 The change in mean PBAC and endometrial thickness in two groups were compared using unpaired t-test. 150 98.45 Statistical significance was taken at p value ≤ 0.05. 100

RESULTS 50 9.8 6.7 9.0 10.1

0

300 258.44 250

200 Score PBAC Endometrial

150 Thickness(mm) Heamoglobin(g/dl) 100 54.24 Pre Treatment Post Treatment

50 9.4 5.8 8.8 10.4 Value 0 Figure 3: Pre-treatment and post-treatment values in

Group B (Combined OCPs). Mean

There was no major side effect with Ormeloxifene. PBAC Score PBAC Amenorrhea was the main symptom seen in 5 cases (18.5%). Nausea, vomiting, ovarian cysts and headache Haemoglobin(g/dl) were other side effects, but neither was significant enough to stop the therapy. In patients receiving combined oral contraceptive pills main symptom was

Pre Treatment Thickness(mm) Endometrial Post Treatment gastric upset (in 32% of cases). Breast tenderness and weight gain were other symptoms. Figure 2: Group A (Ormeloxifene) Comparison between pre-treatment and post treatment Values. DISCUSSION

Out of these 72 patients of DUB 17 were lost to follow up The problem of dysfunctional uterine bleeding i.e. and hence were excluded from the study. In excessive or prolonged regular or irregular menstrual Ormeloxifene group (group A, N=27), patients showed a bleeding in the absence of overt uterine pathology,

International Journal of Reproduction, Contraception, Obstetrics and Gynecology Volume 7 · Issue 9 Page 3612 Luthra S et al. Int J Reprod Contracept Obstet Gynecol. 2018 Sep;7(9):3610-3614 endocrine or haematological disorder is a common reason The results of the present study showed that there was a for consultation in gynaecological out-patient significant rise of haemoglobin of 1.6gm/dl (p <0.0001) departments. In recent years basic physiological research after three months treatment with Ormeloxifene. It is has resulted into a greater depth of insight into the consistent with other studies. Dhananjay BS et al, 2012 mechanisms involved in the control of normal showed that there was a statistically significant increase menstruation and the pathophysiology of dysfunctional in the haemoglobin level (p <0.001) after the treatment uterine bleeding (DUB). with ormeloxifene.13 Agarwal, et al also concluded that mean pretreatment Hb concentration significantly DUB can occur at any time between puberty to increased from 9.04gm% to 10.01 gm% at 3 months and menopause and may be either ovulatory or anovulatory. to 10.86 gm% at 6 months (p <0.0001) in patients of A history of excessive bleeding with regular menstrual DUB treated with Ormeloxifene.14 cycles is usually associated with ovulation. An anovulatory pattern of bleeding with erratic intervals Shravage et al, found that the mean pre-treatment between menstrual periods can also occur. Typically, the endometrial thickness was reduced from 7.81 mm to 4.94 anovulatory pattern occurs at puberty prior to the onset of mm after 3 months of therapy.12 Dhananjay BS et al, regular menstruation and also in women in their mid-30s 2012 showed that there was a statistically significant onwards. It may also be seen in women with PCOD reduction in the endometrial thickness (p< 0.001) after where there is peripheral conversion of androgens to the treatment with ormeloxifene.13 estrogens. Ovulatory bleeding patterns are more common than anovulatory. In present study mean pre-treatment endometrial thickness reduced from 9.4mm to 5.8mm after treatment, Newer drug therapies and the development of less showing a significant reduction (p<0.0001). A total of invasive surgical techniques are in need of further clinical about 81% of patients responded well with Ormeloxifene. trials. The approach to management is to ensure general The results were corresponding to the results of above well-being and improve quality of life in addition to mentioned studies. control the bleeding. Medical management and avoidance of surgery is always recommended, as the short period of CONCLUSION drug therapy bridges the temporary phase of menstrual alterations successfully, wherein young subjects settle From above observations, it can be concluded that the down with normal cycles and elderly subjects attain ormeloxifene is more effective than combined oral menopause. Ormeloxifene can be a good option with its contraceptive therapy in controlling the menstrual blood properties of creating a hypoestrogenic environment loss in cases of DUB. Apart from its efficacy, without disturbing other estrogenic positive effects. Side Ormeloxifene has shown its superiority by good effects like weight gain or breast tenderness, depression, compliance and less stringent eligibility criterion. Thus, it mood changes, mastalgia and poor libido are not there may be considered for the medical management of with Ormeloxifene. It is also devoid of androgenic ill idiopathic menorrhagia, especially in peri-menopausal effects such as acne and hirsutism. Being a metabolically women, in adolescents and in women who wish to non-controversial agent, complications such as preserve their fertility. hypertension, coagulation disorders, hyperglycemia and abnormal lipid profile, which are common with combined Funding: No funding sources OCP, do not occur. Conflict of interest: None declared Ethical approval: The study was approved by the Ormeloxifene also offers perimenopausal bone and Institutional Ethics Committee cardiovascular protection. It is found oncologically protective to the breast and the endometrium. REFERENCES

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